JP5295760B2 - Rna用の注入溶液 - Google Patents
Rna用の注入溶液 Download PDFInfo
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- JP5295760B2 JP5295760B2 JP2008511654A JP2008511654A JP5295760B2 JP 5295760 B2 JP5295760 B2 JP 5295760B2 JP 2008511654 A JP2008511654 A JP 2008511654A JP 2008511654 A JP2008511654 A JP 2008511654A JP 5295760 B2 JP5295760 B2 JP 5295760B2
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- Prior art keywords
- mrna
- rna
- injection
- lactate
- buffer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
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Description
i)細胞内へ導入されるRNAは、ゲノムに挿入されない(これに対し、DNAは、一定量ゲノムに挿入され、これにより、宿主細胞ゲノムの無傷な遺伝子に挿入される。その結果、この遺伝子が変異し、遺伝情報が部分的もしくは全部欠損するか、もしくは情報が誤り得る)。
ii)RNAの効率的な転写のために、プロモーターなどといった、ウィルスの配列を必要としない(これに対し、細胞内に導入されたDNAの発現のためには、強力なプロモーター(例えばウィルスのCMVプロモーター)が必要になる。宿主細胞ゲノムへこのようなプロモーターを挿入することにより、遺伝子の発現制御に予期しない変化が生じる。)。
iii)導入されたRNAの消化は、限られた時間(数時間)に起きる11,12 。このため、一過的な遺伝子発現を実現することができる。この発現は、必要な治療期間後に、中断され得る(これに対し、ゲノムに挿入されたDNAでは、これは不可能である)。
iv)RNAにより、患者に病原性抗RNA抗体が導入されない(これに対し、抗DNA抗体の導入により、望ましくない免疫応答が起きることが知られている)。
v)RNAは、広範に利用できる。ワクチン接種のために、患者個人ベースで、所望の所定タンパクのための任意の所望のRNAが、間際に調製され得る。
を包含する。
‐Proのコドンは、CCUまたはCCAから、CCCまたはCCGへ改変され得る。
‐Argのコドンは、CGU、CGA、AGAまたはAGGから、CGCまたはCGGへ、改変され得る。
‐Alaのコドンは、GCUまたはGCAから、GCCまたはGCGへ、改変され得る。
‐Glyのコドンは、GGUまたはGGAから、GGCまたはGGGへ、改変され得る。
‐Pheのコドンは、UUUからUUCへ改変され得る。
‐Leuのコドンは、UUA、UUG、CUUまたはCUAから、CUCまたはCUGへ、改変され得る。
‐Serのコドンは、UCU、UCAまたはAGUから、UCC、UCGまたはAGCへ、改変され得る。
‐Tyrのコドンは、UAUからUACへ改変され得る。
‐Cysのコドンは、UGUからUGCへ改変され得る。
‐Hisのコドンは、CAUからCACへ改変され得る。
‐Glnのコドンは、CAAからCAGへ改変され得る。
‐Ileのコドンは、AUUまたはAUAから、AUCへ改変され得る。
‐Thrのコドンは、ACUまたはACAから、ACCまたはACGへ、改変され得る。
‐Asnのコドンは、AAUからAACへ改変され得る。
‐Lysのコドンは、AAAからAAGへ改変され得る。
‐Valのコドンは、GUUまたはGUAから、GUCまたはGUGへ、改変され得る。
‐Aspのコドンは、GAUからGACへ改変され得る。
‐Gluのコドンは、GAAからGAGへ改変され得る。
‐終止コドンUAAは、UAGまたはUGAへ改変され得る。
‐オリジナル配列(野生型mRNA)におけるThrをコードする全てのコドンをACC(またはACG)に置換する。元々Serをコードする全てのコドンをUCC(UCGまたはAGC)に置換する、
‐オリジナル配列におけるIleをコードする全てのコドンをAUCに置換する。元々Lysをコードする全てのコドンをAAGに置換する。元々Tyrをコードする全てのコドンをUACに置換する、
‐オリジナル配列におけるValをコードする全てのコドンをGUC(またはGUG)に置換する。元々Gluをコードする全てのコドンをGAGに置換する。元々Alaをコードする全てのコドンをGCC(またはGCG)に置換する。元々Argをコードする全てのコドンをCGC(またはCGG)に置換する、
‐オリジナル配列におけるValをコードする全てのコドンをGUC(またはGUG)に置換する。元々Gluをコードする全てのコドンをGAGに置換する。元々Alaをコードする全てのコドンをGCC(またはGCG)に置換する。元々Glyをコードする全てのコドンをGGC(またはGGG)に置換する。元々Asnをコードする全てのコドンをAACに置換する、
‐オリジナル配列におけるValをコードする全てのコドンをGUC(またはGUG)に置換する。元々Pheをコードする全てのコドンをUUCに置換する。元々Cysをコードする全てのコドンをUGCに置換する。元々Leuをコードする全てのコドンをCUG(またはCUC)に置換する。元々Glnをコードする全てのコドンをCAGに置換する。元々Proをコードする全てのコドンをCCC(またはCCG)に置換する、等といった置換が用いられる。
図1から図5において示されている実験において、Photinus属pyralis種のルシフェラーゼをコードするmRNA(図4の100μlのPBSにおけるpDNA)を含んでいる、それぞれの場合に示されている100μlの緩衝液(緩衝液の組成は、下記の(材料)の1.注入緩衝液の項に与えられている)が、BALB/cマウス13の耳介の中に皮内的に注入された。完全なマウスの耳のルシフェラーゼ活性が測定された。上記ルシフェラーゼ活性は、100万分子のルシフェラーゼを単位として表されている。ルシフェラーゼ活性の検出限界は、この図表において、数値が振られた太線によって示されている。この図表の点のそれぞれは、単一の耳のルシフェラーゼの発現を示している。図に与えられている短い棒は、種々の群の平均値を表している。(マンホイットニー検定にしたがって)上記平均値同士の間に有為に差がある群に対してp値が与えられている。図1、2および5の実験において、上記耳は、注入後15時間において取り出された。示されているこのデータは、各群に対して少なくとも3回の独立した実験から得た結果である。
%相対的なルシフェラーゼ活性(RLA)=(規定のCaCl2 濃度を有する試料のRLA−単なる溶解緩衝液のRLA)/(CaCl2 を有していない試料のRLA−単なる溶解緩衝液のRLA)×100%
にしたがって、計算された。比較的に高濃度のCa2+イオンの存在は、ルシフェラーゼの酵素活性を増強することはなかった。
eGFPのmRNAまたはlacZのmRNAのみを用いた単独トランスフェクション;
個々にトランスフェクトされた細胞(eGFP/lacZ)の混合物;および
2重にトランスフェクトされた細胞(eGFP+lacZ)
が解析された。
‐材料‐
<1.注入緩衝液>
以下の緩衝液を用いた:
2×リン酸緩衝液(PBS)
(PBS=274mMの塩化ナトリウム、5.4mMの塩化カリウム、20mMのリン酸水素2ナトリウム、4mMのリン酸2水素カリウム、20.8℃においてpH7.3)
2×HEPES緩衝液(HBS)
(HBS=300mMの塩化ナトリウム、20mMのHepes、20.8℃においてpH7.3)
1×乳酸塩を含まないRL注入緩衝液
(他の組成および濃度が示されていなかった場合、82.2mMの塩化ナトリウム、4.3mMの塩化カリウム、1.44mMの塩化カルシウム)
1×乳酸塩を含むRL注入緩衝液
(他の組成および濃度が示されていなかった場合、102.7mMの塩化ナトリウム、5.4mMの塩化カリウム、1.8mMの塩化カルシウム、20mMの乳酸ナトリウム)
1×乳酸塩を含み、塩化ナトリウムを含まないRL注入緩衝液
(他の組成および濃度が示されていなかった場合、4.3mMの塩化カリウム、1.44mMの塩化カルシウム、22.4mMの乳酸ナトリウム)
1×乳酸塩を含み、塩化カリウムを含まないRL注入緩衝液
(他の組成および濃度が示されていなかった場合、82.2mMの塩化ナトリウム、1.44mMの塩化カルシウム、22.4mMの乳酸ナトリウム)
1×乳酸塩を含み、塩化カルシウムを含まないRL注入緩衝液
(他の組成および濃度が示されていなかった場合、82.2mMの塩化ナトリウム、4.3mMの塩化カリウム、22.4mMの乳酸ナトリウム)。
全ての動物実験を、制度的指針および大綱的指針にしたがって実施した。8〜15週齢の雌のBALB/cマウスを、チャールス・リバー(スルズフェルド、ドイツ)から入手した。
健康な男性の志願者を用いて人体実験を実施した。この志願者は、この調査の背景および起こりうる結果の説明を受け、同意した。
‐mRNA‐
「キャップされた」mRNAを、インビトロでのT7RNAポリメラーゼ(T7‐オプチmRNAキット(T7-Opti mRNA kits) 、キュアバック(CureVac) 、テュービンゲン、ドイツ)を用いた「ラン‐オフ」転写により調製した。
エンドトキシンフリーのpCMV‐lucDNAを、エンドフリー・プラスミド・マキシ・キット(EndFree Plasmid Maxi Kit(キアゲン、ヒルデン、ドイツ))を用いて調製した。酢酸アンモニウムを用いてpDNAを沈殿して、最終的に、水に滅菌状態で再懸濁した。pGL3(受入番号U47295)のXbaI‐HindIII断片を、pCMV‐HB‐S(受入番号A44171)のNsiI‐HindIIIより消化されたプラスミドに挿入することによって、pCMV‐lucプラスミドを改変した。なお、上記XbaIおよびNsiIの部位は、クレノー断片を用いて平滑末端化されていた。pDNAのレポーター遺伝子は、CMVプロモーターの制御下であった。
保存溶液を、滅菌水においてmRNAまたはDNAを希釈することによって調製した。そして、260nm、280nm、および、320nmにおける分光分析によって濃度と純度とを測定した。
全ての核酸試料では、分光分析によって濃度を測定し、ホルムアルデヒド‐アガロース電気泳動によりmRNAの品位を、または、制限消化およびTBE‐アガロース電気泳動によりDNAの品位を検査した(図10)。品位に加えて、全ての核酸試料の翻訳能力をBHK21細胞の電気穿孔法により分析した。このために、10μgの核酸を含む200μlのPBSが入った0.4cmのキュベットにおいて、300Vおよび150μFで、100〜300万個の細胞を電気穿孔した。トランスフェクトされた細胞における、電気穿孔後の8〜24時間のタンパク質発現を、適切な検出方法(X‐gal染色または発光の検出)によって解析した(図10)。インビボでの実験では、BHK21細胞においてタンパク質発現を示し、且つ、ゲル電気泳動において品位が適切である核酸試料だけが、注入された。
HBSおよびPBSでは、mRNAを1×濃縮緩衝液に希釈した。乳酸塩を含有するか、または、含有しないRL注入緩衝液、および、乳酸塩を含有するRL注入緩衝液の(Ca2+、K+、およびNa+の1つが欠乏している)各変形物では、mRNAを0.8×濃縮緩衝液に希釈した。なお、これらのRL注入緩衝液の組成および濃度は、‐材料‐の<1.注入緩衝液>を参照のこと。別の方法が示されない限り、マウスの耳1つ当たりに、20μgのmRNAを含む100μlの注入緩衝液を用いた。mRNAの2次構造を取り除くために、RNA注入溶液を5分間80℃で加熱した。それから、このRNA注入溶液をさらに5分間氷上に置いた。最後に、RNA注入溶液をSub‐Q(ベクトン・ディッキンソン、ハイデルブルグ、ドイツ)注射器の中に吸引した。別々の注射器を、各注入に用いた。プラスミドDNA(pDNA)を1×濃縮PBSに希釈した。
エキソビボでのルシフェラーゼ活性を検出するために、組織の溶解物を調製した。このために、乳棒と乳鉢とを用いて液体窒素下において組織を粉砕して、残存する「塊」を800μlの溶解緩衝液中において均一化した。上記溶解緩衝液の組成は、25mMのTris HCl、2mMのEDTA、10%(w/v)のグリセリン、1%(w/v)のTritonX‐100、ならびに、添加されたての2mMのDTTおよび1mMのPMSFである。小型遠心分離機にて4℃で10分間、13000rpmで遠心することによって、ホモジュネートの上清を得た。この溶解物の110μlのアリコートを−80℃で保存した。
生きている動物におけるルシフェラーゼの注入物を検出するため、核酸注入後に特定の時間においてマウスを麻酔した。マウスを3つの異なる群に分割した。マウスの群Iでは、100μlのRL注入溶液を左耳に注入して、ルシフェラーゼをコードするmRNAを20μg含む100μlのRL注入緩衝液を左耳に注入した。群IIでは、ルシフェラーゼをコードするmRNAを20μg含む100μlのRL注入緩衝液を左耳および右耳のそれぞれに注入した。マウスの群IIIでは、100μlのRL注入緩衝液を右耳に注入して、ルシフェラーゼをコードするmRNAを20μg含む100μlのRL注入緩衝液を左耳に注入した。それから、フィルター滅菌された20mg/mlのルシフェリン(シンケム(Synchem) 、カッセル、ドイツ)のPBS(フィルター滅菌済み)を200μl、マウスの腹腔内に注入した。ルシフェリンの注入から5分後に、マウスの光の放出を20分間集めた。このために、マウスを暗い箱の中の予め37℃に加熱されたプレートに配置した。なお、左側が群Iであり、中央が群IIであり、右側が群IIIである。上記箱には、エクオリア・マクロイメージングカメラ(浜松、日本)が備えられていた。光の放出は擬似カラーイメージにて示され、このイメージに普通の光の下でのマウスのグレースケールイメージが重ね合わされた。ルシフェラーゼをコードするmRNAを20μg含有する、(i)乳酸塩を含むRL注入緩衝液、または、(ii)乳酸塩を含み、塩化ナトリウムを含まないRL注入緩衝液、(iii)乳酸塩を含み、塩化カリウムを含まないRL緩衝液、および、(iv)乳酸塩を含み、塩化カルシウムを含まないRL緩衝液、を用いて同じ実験を同じように行った。
毛が剃られたマウスの耳を切り裂き、ティッシュ‐テック(Tissue-Tek(登録商標))O.C.T(登録商標)コンパウンド(サクラ社(Sakura)、ズーテルヴァウデ(Zoeterwuode) 、オランダ)を含む溶媒に包埋して、−80℃で保存した。これらのブロックに由来する、20の厚さ20μmの横断面の連続凍結切片を、スパーフロストプラス標本保持器(SperFrost (登録商標)plus specimen holder、ランゲンブリンク(Langenbrinck)、エメンディンゲン、ドイツ)に、1組のうちの2つの切片間の垂直距離が約100μmになるように5組配置した。それから、上記切片を空気乾燥して、染色するまで−20℃で保存した。移送されたmRNA(大腸菌のβ‐ガラクトシダーゼ)が取り込まれて、翻訳される領域を1次スクリーニングするために、X‐galと一緒に1組の切片を染色した。このために、上記標本保持器を室温に曝して、ImmEdge(登録商標)ペン(ベクター(Vektor)、バーリンゲーム、米国)を用いて輪郭を描いた。それから2%ホルマリンを含むPBSに15分間浸すことにより、切片を固定した。PBS中に標本保持器を2分間浸すことを3回繰り返して、標本保持器を洗浄した。その後、湿度室において、一晩37℃で、X‐gal染色溶液とインキュベートすることにより染色した。ここで、X‐gal染色溶液の組成は、添加されたての1mg/mlのX‐gal、5mMのフェリシアン化カリウム、5mMのフェロシアン化カリウム、1mMの塩化マグネシウム、15mMの塩化ナトリウム、60mMのリン酸1水素2ナトリウム、および、40mMのリン酸2水素ナトリウムである。上記標本保持器の2分間の洗浄を2回行い、ハイドロ‐マトリックス(Hydro-Matrix(登録商標)、マイクロ‐テック‐ラボ(Micro-Tech-Lab)、グラーツ、オーストリア、水で2倍に希釈)溶媒を用いて上記標本保持器を処理することによって、染色を終了させた。
健康な男性の志願者により、この実験が実施された。注入部位の毛を剃り、殺菌を行い、RnaseZap(アンビオン、オースチン、米国)溶液を用いて処理した。それから、120μgのmRNAを含む0.8×RL注入緩衝液を、1バッチにおいて全容積の200μlで、注入した。さらに同様のバッチにおいて、RL注入緩衝液に替わって、(i)乳酸塩を含み、塩化ナトリウムを含まないRL注入緩衝液、(ii)乳酸塩を含み、塩化カリウムを含まないRL注入緩衝液、および、(iii)乳酸塩を含み、塩化カルシウムを含まないRL注入緩衝液を用いた。
2つの異なる群の平均値を、いわゆる「ノンパラメトリックなマンホイットニーの順位和検定」により比較した。0.05よりも小さいp値は、有意差としてみなされ、図に示されている。
細胞種に特異的な染色と、mRNAの移送の検出とを同時に可能にする組織学的な処理を用いて、インビボにおいてmRNAを取り込み、且つ、発現する細胞種を同定した。
マウスの耳の薄い切片を調製して、全ての細胞が藍色染色処理において単一層に存在していることを確かめた。(i)マウスの耳の筋肉の形態(約0.5mm〜約1mmの厚みの薄層)、(ii)凍結切片のみを用いることができること(パラフィン切片の調製に必須であるいくつかの工程の間にβ‐ガラクトシダーゼは、加熱により不活性化される)、および、(iii)切片とできるだけ多くの高品質なサブ切片とが必要とされることに注意すると、これらの切片の調製は、非常に困難であることが判明した。それにもかかわらず、20μmの厚みを有する良質のいくつかの組の切片を、調製することができた。2つの異なる染料を用いてβ‐ガラクトシダーゼの活性を検出した。陽性細胞が青緑に染色されるX‐galの方が、陽性細胞が紫に染色されるマゼンタ‐galよりも良好なコントラストを示す結果になった。しかしながら、これと同時に、(例えば毛包によって引き起こされる)バックグラウンドの非特異的な染色が、X‐gal染色では非常に目立った。それでもなお、mRNAの移送の明確な区別が可能であった。マゼンタ‐gal染色では、バックグラウンドの非特異的な染色は、目立たなかった。
mRNAの移送の染色(藍色染料)と細胞特異的なマーカーの染色(特異的抗体)の組み合わせは、固定剤および組み合わされた染色の手順(藍色染色は37℃で14時間のインキュベートを含む)に関するいくつかの適応を要求する。第1にアセトンを用いて固定を行い、その後抗体染色を行った場合に、MHCII分子に対する抗体染色の最良の結果が得られた。これに反して、第1にホルムアルデヒドとグルタルジアルデヒドとの混合物を用いて固定を行い、その後藍色染色を行った場合に、β‐ガラクトシダーゼの活性に対する最良の結果が得られた。これらの様々な事情を考慮して、次の処理を選択した。すなわち、グルタルジアルデヒドを用いずに、ホルムアルデヒドを用いて固定を行い、抗体染色を行った。グルタルアルデヒドにより組織の自己蛍光が劇的に増加するので、グルタルアルデヒドが、藍色染色の質に対して僅かな効果をもしも有しているときは、グルタルアルデヒドを除外する必要があった。次のいくつかの理由から、ホルムアルデヒドを用いる固定を用いた:
1.アセトンを用いた固定よりも、組織の形態がより良好に保護される、
2.メリハリがあり、且つ、強い藍色染色には、ホルムアルデヒドを用いる固定が要求される、そして、
3.それにもかからわらず、抗MHCII抗体の染色の質は、ホルムアルデヒドを用いても許容できる。
2つの異なる染色の組み合わせには、2つのプロトコールの様々な工程の適合性だけでなく、検出に用いられるプローブの適合性も要求される。原理上は、免疫染色に沈殿性の染料(酵素プローブ)、または、蛍光染料(標識されたプローブ)を用いることが可能である。藍色染色と沈殿性の染料とを組み合わせるために、X‐galとAECとを用いた。そのような染色では、2重に陽性を示す細胞は、黒色にみえた(図15 8)。これでは、個々の陽性細胞を強度によって区別することは困難である。そのため、蛍光染料のアレクサ・フルオロ(Alexa Fluor) 546とマゼンタ‐galとの組み合わせが好ましい。次の2つの理由から、X‐galに替えてマゼンタ‐galを用いることが好ましい:
1.(染料が飽和量で添加されたときであっても)マゼンタ‐galの染色強度は非常に弱かった、
2.マゼンタ‐galの陽性細胞の色は、アレクサ・フルオロ546の蛍光染料の発光波長とより良好に調和した。
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Claims (15)
- 宿主生物内のmRNA翻訳を増加させるために皮内投与または皮下投与されるRNA注入溶液を調製する際の、mRNA、及び水性溶液の利用であって、
上記水性溶液は、60mMから500mMまでの塩化ナトリウム(NaCl)、0.01mMから80mMまでの塩化カルシウム(CaCl2)、及び必要に応じて4mMから300mMまでの塩化カリウム(KCl)を含有する、利用。 - 請求項1に記載の利用であって、
上記水性溶液は、15mMから200mMまでの乳酸塩を含有する、利用。 - 請求項1または2に記載の利用であって、
上記水性溶液は、HEPES、Tris/HCl,Na(K)2 HPO4 /Na(K)H2PO4 等の緩衝系を含有しない、利用。 - 請求項1〜3の何れか1項に記載の利用であって、
上記水性溶液は、単糖類、二糖類、または多糖類を含有しない、利用。 - 請求項1〜4の何れか1項に記載の利用であって、
mRNAは、むき出しのmRNA、またはポリ陽イオンと複合体と成すmRNAである、利用。 - 請求項5に記載の利用であって、
mRNAは、プロタミンと複合体を成す、利用。 - 請求項5または6に記載の利用であって、
mRNAは、少なくとも1つの天然または非天然の改変を有する、利用。 - 請求項7に記載の利用であって、
上記改変は、
コードされるアミノ酸配列を変えずに、mRNAのコード領域のG/C含量を増加させること、
少なくとも1つのリボヌクレオチドアナログを導入すること、
WT配列における非安定化配列を除去すること、または、
リボソーム結合部位の領域のA/U含量を増加させること、からなる群から選択される、利用。 - 請求項1〜8の何れか1項にて定義された、mRNA、及び水性溶液を含有する、宿主生物内のmRNA発現を増加させるための皮内投与または皮下投与されるRNA注入溶液。
- 請求項9に記載のRNA注入溶液であって、
mRNAは、むき出しのmRNAである、RNA注入溶液。 - インビトロまたはエキソビボにおいて、細胞内におけるmRNAのmRNA翻訳を増加させる方法であって、上記方法は、次の工程、
a.請求項9または10に記載のmRNA注入溶液を調製、及び
b.工程a.のmRNA注入溶液の、細胞への投与、
を含む、方法。 - 請求項11に記載の方法であって、
上記細胞は、マウス、ラット、ブタ、ウシ、ウマ、イヌ、ネコ、サル、およびヒトからなる群より選ばれる哺乳類の細胞である、方法。 - 請求項12に記載の方法であって、
上記哺乳類は、ヒトである、方法。 - 細胞のインビトロトランスフェクション方法であって、
請求項9または10に記載の注入溶液が、必要に応じてエレクトロポレーションにより、細胞に投与される、方法。 - 請求項14に記載の方法であって、
上記細胞が、実験細胞または患者の細胞である、方法。
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CN101203245B (zh) | 2012-11-07 |
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EP3583953B1 (de) | 2023-06-28 |
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US20080267873A1 (en) | 2008-10-30 |
AU2006249093B2 (en) | 2013-09-19 |
RU2418593C2 (ru) | 2011-05-20 |
RU2007146610A (ru) | 2009-06-27 |
DE102005023170A1 (de) | 2006-11-23 |
AU2006249093A1 (en) | 2006-11-23 |
EP1881847A2 (de) | 2008-01-30 |
EP3153179A1 (de) | 2017-04-12 |
EP3153179B1 (de) | 2019-06-19 |
JP2008540601A (ja) | 2008-11-20 |
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